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A-412,997 - Highly selective Dopamine receptor 4 agonist

add; adhd; stimulant; research;

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#1 Mind_Paralysis

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Posted 04 November 2014 - 06:53 PM


This little chemical has recently been getting on my mind quite a bit... it almost seems like a dream come true, even! A stimulant which doesn't give the usual side-effects - since it has such a highly selective mode of effect - it only agonises ONE receptor - and it so happens to be, precisely the most common faulty receptor in the ADHD -brain!

 

No heart-palpitations, no suicidal tendencies, no sweating, no itching, no nothing! One bullet - one kill.

 

http://en.wikipedia.org/wiki/A-412,997

 

 

A-412,997 is a drug which acts as a dopamine agonist that is used in scientific research. It is the first drug developed that is a highly selective agonist for the D4 subtype, with significantly improved selectivity over older D4-preferring compounds such as PD-168,077 and CP-226,269.[1] In animal tests it improved cognitive performance in rats to a similar extent as methylphenidate, but without producing place preference or other signs of abuse liability.[2][3] Also unlike other dopamine agonists, selective D4 agonists do not cause side effects such as sedation and nausea, and so might have advantages over older dopamine agonist drugs.[4]

 

A-412%2C997.png

 

SO! Anybody here who has more info on this? Such as if it's going through any trials as a new ADHD -med? I mean, the application seems obvious.

 

Perhaps there's even someone here who has experience with this drug? That would be outstanding, I must say!



#2 ZHMike

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Posted 04 November 2014 - 07:01 PM

Good find, hopefully someone has more info... the studies are from like 2005 and 2008, nothing new since then which is kinda weird. 



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#3 Mind_Paralysis

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Posted 24 April 2015 - 10:49 AM

Bumping this, because I've been coming up short on further research on this chemical. All I know is that there is a clear overlap between the penile erection effects and the cognitive effects - i.e, a definitive side-effects for most male users of this compound would be painful boners.

 

On the other hand, that appears to be the only noted side-effect.

 

So, anybody got some new research on this?



#4 Metagene

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Posted 24 April 2015 - 06:25 PM

Here's a study from 2014

Putative therapeutic targets for symptom subtypes of adult ADHD: D4 receptor agonism and COMT inhibition improve attention and response inhibition in a novel translational animal model

http://www.europeann...0327-7/abstract

Pages 90-112: https://docs.google....sp=docslist_api

Edited by Metagene, 24 April 2015 - 06:45 PM.


#5 Metagene

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Posted 24 April 2015 - 09:40 PM

Bumping this, because I've been coming up short on further research on this chemical. All I know is that there is a clear overlap between the penile erection effects and the cognitive effects - i.e, a definitive side-effects for most male users of this compound would be painful boners.

 

On the other hand, that appears to be the only noted side-effect.

 

So, anybody got some new research on this?

 

I started to think penile erections were a result of A-412997 being injected directly into the paraventricular nucleus. Nope. Same result with subcutaneous administration. A-412997 and PIP3EA are actually more potent than PD168077 when delivered systemically. RO-10-5824 might be the way to go if you want to side step painful boners.

 

"A-412997 induced penile erection in conscious rats when
administered subcutaneously with a maximal effect at 0.1
Amol/kg whether the percent incidence (percent of rats
having at least one erection) or the number of penile
erections was determined
(Fig. 4 Panels A and B, respectively).
The maximum effective dose was 0.1 Amol/kg
with a latency time to erection of 19 min. Apomorphine at
the maximum effective dose 0.1 Amol/kg) gave comparable
results to A-412997. PD168077 and CP226269 also induce
penile erection in rats when dosed systemically with
maximum effective doses of 0.3 and 1.0 Amol/kg, respectively
(Hsieh et al., 2004). The erectogenic effects of A-
412997 could be blocked by systemic pretreatment with
either clozapine (1–10 Amol/kg i.p.) (Fig. 4C) which blocks
the rat dopamine D4 receptor in vitro.
In all three clozapine
treatments, the percent incidence of penile erection was no
different than rats without 0.1 Amol/kg A-412997."

 

"The partial D4 agonist RO-10-5824 (intrinsic activity=0.36)
showed trends toward increasing novel exploration in mice,
but the effects did not reach significance (Powell et al.,
2003).
It will be of interest to repeat these studies using A-
412997, a full D4 agonist. Recently, ABT-724, a selective
dopamine D4 receptor agonist has been described that
induces penile erection in rats. While the selectivity profiles
are comparable, ABT-724 differs from A-412997 in that the
latter is a partial agonist in the rat (0.62 vs. 0.82 intrinsic
activity at rat D4 in calcium flux assays) (Brioni et al.,
2004).
"

 

 

A-412997 is a selective dopamine D4 receptor agonist in rats

 

https://drive.google...iew?usp=sharing

 

 

PIP3EA and PD-168077, two selective dopamine D4 receptor agonists, induce penile erection in male rats: site and mechanism of action in the brain.

 

http://www.ncbi.nlm....pubmed/17067298


Edited by Metagene, 24 April 2015 - 09:51 PM.

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#6 Area-1255

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Posted 02 May 2015 - 02:08 AM

Interesting, I've written small references to this compound in multiple situations. 

 

Unfortunately, it's another one of those ideas that can't be made into an available experiment without certain 'resources'.

However, if tht.co comes back up and released way 100 635 - then we've taken care of this issue as it acts AS a dopamine D4 agonist plus 5-HT1A antagonist..which would be DOUBLE the pro-cognitive and double the aphrodisiac effects!


Edited by Area-1255, 02 May 2015 - 02:09 AM.

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#7 Junk Master

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Posted 04 May 2015 - 04:42 AM

Let's keep this find on the front burner, it really could be something!


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#8 Mind_Paralysis

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Posted 11 May 2015 - 09:30 PM

Interesting, I've written small references to this compound in multiple situations. 

 

Unfortunately, it's another one of those ideas that can't be made into an available experiment without certain 'resources'.

However, if tht.co comes back up and released way 100 635 - then we've taken care of this issue as it acts AS a dopamine D4 agonist plus 5-HT1A antagonist..which would be DOUBLE the pro-cognitive and double the aphrodisiac effects!

 

Hold up - to what extent does WAY-100,635 antagonize Serotonin? My genetic testing showed that I most likely have a problem with my serotonin-processing, which could be the reason why I have depressive and anxiogenic symptoms with long-term stimulant-use.

 

Antagonising my Serotonin-receptors doesn't seem like a very good idea, in that case...

 

On the one hand, my gene-testing did show that I have the DRD4 mutation associated with ADHD, and I have been diagnosed with ADHD-PI - hence, I know that agonizing that particular receptor is beneficial for me, personally.

 

 

So, WAY-100,635 may not be for me - a purer, partial D4-agonist is probably preferable to some patient-groups.

 

And no, I don't need the aphrodisiac effects either - quite the contrary, I'm afraid. It's even a hindrance in my personal life at times. >_<


Edited by Stinkorninjor, 11 May 2015 - 09:32 PM.


#9 lourdaud

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Posted 31 May 2016 - 03:14 PM

Hey, has anyone found out anything more about any D4 agonists?
I'd be up for a group buy even if it'd be very expensive!



#10 gamesguru

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Posted 31 May 2016 - 10:46 PM

the Alkaloid Nuciferine. ... a partial agonist at D2, D5 and 5-HT6, an agonist at 5-HT1A and D4 receptors, and inhibited the dopamine transporter
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#11 lourdaud

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Posted 01 June 2016 - 02:42 PM

Partial agonist? Much like an atypical anti-psychotic then? https://en.wikipedia...wiki/Nuciferine



#12 Mind_Paralysis

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Posted 27 June 2016 - 10:51 AM

Partial agonist? Much like an atypical anti-psychotic then? https://en.wikipedia...wiki/Nuciferine

 

I would believe so. This might actually be a very useful compound for treating Schizophrenia, since D4-agonists are reported to help with negative symptoms without triggering mania and psychosis, like other dopamine-agonists.

 

the Alkaloid Nuciferine. ... a partial agonist at D2, D5 and 5-HT6, an agonist at 5-HT1A and D4 receptors, and inhibited the dopamine transporter


I don't think this is the way to go - it's far too unselective in its action, we may find that at certain doses, this compound impairs cognition too much in certain aspects, compared to the value it adds in increasing cognition in other aspects.

 

Anyways, here's the binding-profile, but I'm having a hard time interpreting it... Can some of you give your thoughts on this one?

 

http://journals.plos...ne-0150602-g002


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#13 gamesguru

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Posted 27 June 2016 - 03:08 PM

yes, it should work similar to abilify. not usually effective on its own, but more of an adjunctive or even off-label med.  overall, very promising alkaloid.

 

the 5-ht6 is going to cause cognitive deficits, which can however be reversed by bacopa (5-ht6 antagonist).  you can see some good things about D4 as a novel ADHD med [1]. as well, it's hard to talk sh*t about D5 [2]. i don't think desensitization at the 5-ht1a site will be a significant concern in healthy people, but perhaps those recovering from PSSD to beware?



#14 Mind_Paralysis

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Posted 27 June 2016 - 04:08 PM

yes, it should work similar to abilify. not usually effective on its own, but more of an adjunctive or even off-label med.  overall, very promising alkaloid.

 

the 5-ht6 is going to cause cognitive deficits, which can however be reversed by bacopa (5-ht6 antagonist).  you can see some good things about D4 as a novel ADHD med [1]. as well, it's hard to talk sh*t about D5 [2]. i don't think desensitization at the 5-ht1a site will be a significant concern in healthy people, but perhaps those recovering from PSSD to beware?

 

The link I posted shows the binding affinity of the compound to a lot of receptors, Aripiprazol (abilify) is included in the comparison-chart. Could you please have a look and help me get a grasp on how big the D4-agonism is? As compared to the binding-affinity to the other receptor-types.

 

It might be worth it to use this, if it's actually selective enough for D4 - once you go past a certain threshold it's bound to be beneficial.



#15 gamesguru

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Posted 27 June 2016 - 05:57 PM

i suffer multiple forms of colorblindness, so fast luck i am the one to decipher it...

but its D2 effect seems comparable to clozapine's which is weak. moreover (colorblindness not tricking me), the dopamine effect is weaker than the effect at 5-HT1A, 2C, or 7.  seems to be slightly active at H2 and across most adrenoreceptors.  the finding of DAT inhibition is not repeated here, you can see the dopamine transporter is clearly red.

 

i guess looking at that receptor binding profile, Nuciferine is very non-selective and promiscuous. sorry guys.



#16 Mind_Paralysis

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Posted 27 June 2016 - 07:50 PM

Haha, colourblind?? Yeah that's fast luck! xD

Anyways, thanks for having a look none the less, the D2-binding affinity is indeed almost identical at -6,35 for both Nuciferine and Clozapine. You set me on my way to interpreting it here.

 

Compared to Wikipedias more traditional binding-table, I can see that the binding affinity for Clozapine to D2 is 157 ki nM. Interestingly enough, Clozapine has the HIGHEST affinity for binding to the D4-receptor out of the D-receptors btw - as an antagonist. So if you're ADHD, better NOT be using that one...!

 

https://en.wikipedia...anism_of_action

 

Right, so Green, the colour of Clozapine's binding to D4 obviously means high then. Ok, gotcha'.

 

When comparing the data to Aripiprazole's official binding, I find that Purple, -9 in the colour-table, responds to a ULTRA-high affinity: 1.6 ki nM!

 

Aripiprazol's binding to D4, which is slightly higher than Nuciferine's, is veeery low: 514 ki nM. I'm going to guess that this means Nuciferine has a binding-profile of around 600 ki nM to D4.

That'... not very selective, if you take into account that it's binding to D2, as an antagonist, is 157 ki nM.

 

Yeah, your assessment is correct Gamesguru - Nuciferine is a tramp!

 

Big cheers for finding it though. = )

 

Now... I recall some SCT fellow on Reddit who experienced greatly improved symptoms from another, new atypical... ALSO similar to Aripiprazol, I believe. I'm gonna' go and try and find that post, see which one it was. Apparently it was a compound which is now on the market! Just launched. Let's see what D4-properties that one has...



#17 Mind_Paralysis

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Posted 27 June 2016 - 08:04 PM

FOUND IT! That other atypical, went under the development-name of OPC-34712.

 

https://www.reddit.c...xine_is/d0glkmz

 

And that drug is REXULTI!

 

Aka Brexpiprazole.

http://mentalhealthd...ession-adjunct/

 

Oddly enough, in contrast to other atypicals, this one really IS FDA-approved as an adjunct to depression, huh. It was also trialled for ADHD but didn't have sufficient effects, so not approved.

 

Let's have a look at the mode of action of this sucker, and the binding-profile...

 

https://en.wikipedia...le#Pharmacology

 

The binding-profile doesn't show any affinity whatsoever to D4... hmm... let's see if I can find some other data.

Apparently Rexulti's partial agonism seems to go more towards blocking than stimulating as well, so I have no idea why that guy had improved symptoms. I can't see anything here that would obviously improve ADHD-PI symptoms.

 

Yeah, these antipsychotics are probably all dead-ends - back on topic! Selective stimulants, please, fellows.

 

 


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#18 gamesguru

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Posted 27 June 2016 - 10:32 PM

i mean, so what its not as active as abilify or haloperidol? you could still increase the dose to the point it does become as active... but unless its D2 or D4 selective, other effects will crop up alongside. now your eyes are better than mine, but it didn't look too selective to me.

 

It [brex] is also an antagonist of the 5-HT2A, 5-HT2B, 5-HT7, α1A-, α1B-, α1D-, and α2C-adrenergic, and H1 receptors.[22] It has negligible affinity for the mACh receptors.[22]

depending on the individual, serotonin has mixed effects, but surely interacts with dopamine and adhd [!].  but the 5-ht7 antagonism actually promotes impulsivity. histamine h3 antagonist is good for adhd, couldn't find anything about h1 tho.







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